US2026078146A1PendingUtilityA1
Epha2 targeting agents and uses thereof
Est. expiryOct 17, 2042(~16.2 yrs left)· nominal 20-yr term from priority
A61K 38/00A61P 35/00A61K 47/64A61K 47/55A61K 45/06C07K 7/08
56
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Claims
Abstract
EphA2 targeting agents developed herein are potent peptide-mimetics with high affinity (Kds 8-20 nanomolar) for the ligand binding domain, called targefrin. Monomeric versions of targefrin act as antagonists while dimeric versions (targefrin-dimer) of the agent cause receptor internalization and degradation via a lysosomal pathway. Hence, targefrin-dimer agents are effective in reducing pro-oncogenic EphA2 levels in cancer cells when used as single agents or in combination with standards of care. Targefrin-dimers can also sensitive cancer cells that developed resistance to EGER or BRAE inhibitors, and potentially other anti-cancer agents. In addition, the dimeric agents can be conjugated with chemotherapy such as paclitaxel to deliver selectively cytotoxic agent to EphA2 expressing cancer cells. Monomeric agents can be linked to chemotherapy via a stable cleavable linker, accumulate the cytotoxic at the tumor, that then would enter the tumor. Novel composition and examples of these applications are reported.
Claims
exact text as granted — not AI-modified1 . A compound of formula (I):
or a salt thereof, wherein:
each R is independently selected from the group consisting of morpholino, piperidino, and piperazine, that is optionally substituted with (C 1 -C 6 )alkyl;
each R 1 is benzyl, 3-indolylmethyl, 4-pyridinylmethyl, 1-naphthylmethyl, or 2-naphthylmethyl, which benzyl, 3-indolylmethyl, 4-pyridinylmethyl, 1-naphthylmethyl, and 2-naphthylmethyl is optionally substituted with one or more groups independently selected from hydroxy, amino, nitro, (C 1 -C 6 ) alkoxy, and (C 1 -C 6 )alkyl;
each R 2 is independently selected from the group consisting of (C 1 -C 6 )alkyl that is optionally substituted with hydroxy;
each R 4 is independently selected from the group consisting of biphenyl and phenoxyphenyl, which biphenyl and phenoxyphenyl is optionally substituted with one or more groups independently selected from halo, hydroxy, (C 1 -C 6 )alkyl, and (C 1 -C 6 ) alkoxy, wherein each (C 1 -C 6 )alkyl and (C 1 -C 6 )alkoxy is optionally substituted with one or more groups independently selected from the group consisting of halo;
each R 7 is (C 1 -C 6 )alkyl that is optionally substituted with hydroxy;
each R 8 is independently selected from the group consisting of isopropyl and (C 3 -C 6 )cycloalkyl;
each R 9 is independently selected from the group consisting of benzyl that is optionally substituted with one or more halo;
R 12 is H or is selected from the group consisting of:
R 100 is H, (C 3 -C 6 )cycloalkyl, or (C 1 -C 6 )alkyl that is optionally substituted with hydroxy;
R 101 is H, (C 3 -C 6 )cycloalkyl, or (C 1 -C 6 )alkyl that is optionally substituted with hydroxy;
R 102 is H, (C 3 -C 6 )cycloalkyl, or (C 1 -C 6 )alkyl that is optionally substituted with hydroxy;
R 103 is -L 1 -D;
D is the residue of a drug or the residue of a targeting agent;
p is 1, 2, or 3;
m is 1, 2, or 3;
n is 1, 2, or 3;
R 104 is:
R 11 is C(═NH)NH 2 ;
L 1 is a linking group; and
L 2 is a linking group.
2 . The compound or salt of claim 1 , wherein;
each R 1 is benzyl, 1-naphthylmethyl, or 2-naphthylmethyl, which benzyl, 1-naphthylmethyl, and 2-naphthylmethyl is optionally substituted with one or more groups independently selected from hydroxy, amino, nitro, and (C 1 -C 6 )alkyl; R 12 is H or is selected from the group consisting of:
R 100 is H, (C 3 -C 6 )cycloalkyl, or (C 1 -C 2 )alkyl;
R 101 is H, (C 3 -C 6 )cycloalkyl, or (C 1 -C 2 )alkyl; and
R 102 is H, (C 3 -C 6 )cycloalkyl, or (C 1 -C 2 )alkyl.
3 . (canceled)
4 . The compound or salt of claim 1 , wherein each R is piperazine, that is optionally substituted with (C 1 -C 6 )alkyl.
5 - 8 . (canceled)
9 . The compound or salt of claim 1 , wherein each R 1 is 2-nitrobenzyl, 4-methylbenzyl, 4-hydroxybenzyl, or 4-aminobenzyl.
10 . (canceled)
11 . The compound or salt of claim 1 , wherein each R 2 is isobutyl or hydroxymethyl.
12 . (canceled)
13 . (canceled)
14 . The compound or salt of claim 1 , wherein each R 4 is independently selected from the group consisting of biphenyl, 2′-trifluoromethylbiphenyl, 2′-methylbiphenyl, 4′-chlorobiphenyl, 2′-methoxybiphenyl, 3′-methylbiphenyl, 2′-methyl-4′-methoxybiphenyl, phenoxyphenyl, and 4-(4-hydroxyphenyloxy)phenyl.
15 . The compound or salt of claim 1 , wherein each R 8 is independently selected from the group consisting of isopropyl and (C 3 -C 6 )cycloalkyl.
16 . (canceled)
17 . The compound or salt of claim 1 , wherein R 12 is H.
18 . The compound or salt of claim 1 , wherein R 12 is:
19 . The compound or salt of claim 18 , wherein R 100 is H, —CH 3 , —C 2 H 5 , i-pr, cyclohexyl, or —CH 2 OH.
20 . The compound or salt of claim 18 , wherein R 101 is H, —CH 3 , —C 2 H 5 , i-pr, cyclohexyl, or —CH 2 OH.
21 . The compound or salt of claim 18 , wherein R 102 is H, —CH 3 , —C 2 H 5 , i-pr, cyclohexyl, or —CH 2 OH.
22 . The compound or salt of claim 1 , wherein R 12 is:
23 - 25 . (canceled)
26 . The compound or salt of claim 1 , wherein L 1 is:
27 - 28 . (canceled)
29 . The compound or salt of claim 1 , wherein D is a residue of a taxane, including paclitaxel, docetaxel, or cabazitaxel.
30 . The compound or salt of claim 1 , wherein D is a residue of gemcitabine
31 - 36 . (canceled)
37 . The compound or salt of claim 1 , wherein L 2 is —CH 2 C(═O)—, —CH 2 CH 2 C(═O)—, —CH 2 CH 2 CH 2 C(═O)—, —CH 2 CH 2 CH 2 CH 2 C(═O)—, or —CH 2 CH 2 CH 2 CH 2 CH 2 C(═O)—.
38 . A compound selected from the group consisting of:
or a salt thereof.
39 . (canceled)
40 . A method for treating cancer in an animal comprising administering a compound or salt of claim 1 to the animal.
41 - 45 . (canceled)Join the waitlist — get patent alerts
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